Antigenic breadth: a missing ingredient in HSV-2 subunit vaccines?

Abstract

The successful human papillomavirus and hepatitis B virus subunit vaccines contain single viral proteins that represent 22 and 12%, respectively, of the antigens encoded by these tiny viruses. The herpes simplex virus 2 (HSV-2) genome is >20 times larger. Thus, a single protein subunit represents 1% of HSV-2’s total antigenic breadth. Antigenic breadth may explain why HSV-2 glycoprotein subunit vaccines have failed in clinical trials, and why live HSV-2 vaccines that express 99% of HSV-2’s proteome may be more effective. I review the mounting evidence that live HSV-2 vaccines offer a greater opportunity to stop the spread of genital herpes, and I consider the unfounded ‘safety concerns’ that have kept live HSV-2 vaccines out of U.S. clinical trials for 25 years.

Keywords::

• alum + monophosphoryl lipid A adjuvant
• antigenic breadth
• deletion of ICP0’s nuclear localization signal
• glycoprotein D
• herpes simplex virus 2
• infected cell protein 0
• live HSV-2 vaccine
• plaque-forming unit
• severe-combined immunodeficiency

Acknowledgements

The author wishes to thank Edward Schmidt for invaluable comments during the writing and revision of this manuscript.

Financial and competing interests disclosure

This work was supported by the Excellence in Academic Medicine Committee of the Southern Illinois University School of Medicine, as well as a grant from the National Institutes of Health to study the Development of an Effective Genital Herpes Vaccine (R21 AI81072). W Halford is a co-author on United States Patent Application Publication US2010/0226940 A1, which describes the uses of herpes simplex virus 2 ICP0- mutants in the design of a live-attenuated HSV-2 vaccine strain. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Most herpes simplex virus 2 (HSV-2) vaccines proposed to date are subunit vaccines that expose the human immune system to 1% of HSV-2’s antigens. Glycoprotein D is the best studied HSV-2 vaccine, but has failed to elicit robust protection against genital herpes in human clinical trials.

• Live HSV-2 vaccines are a logical alternative, but have not been carefully evaluated in US clinical trials due to a myriad of safety concerns, which are not well supported by evidence.

• Live HSV-2 vaccines appear to be 50 times more effective than gD subunit vaccines in preventing genital herpes in mice and guinea pigs.

• The minimal health risks of vaccinating the human population with a live-attenuated HSV-2 vaccine would be preferable to the unchecked spread of wild-type HSV-2.

• Antigenic breadth may explain why past HSV-2 subunit vaccines have failed, and why live HSV-2 vaccines are more likely to succeed in preventing HSV-2 genital herpes.

Notes